Abstract This application focuses on generating additional preclinical characterization data for a synthetic endomorphin analog, MTX1604, and advancing clinical development of this novel analgesic towards FDA approval. MTX1604 is a potent, and highly effective, analgesic that exhibits a robust duration of efficacy in a variety of validated animal models of acute, neuropathic, inflammatory, post-operative, and visceral pain. At analgesic doses in the rat, MTX1604 appears to have reduced reward potential, and has reduced liability of respiratory suppression, tolerance, and impaired motor coordination, as compared to morphine. If this profile can be replicated in the clinic, this compound could have a direct impact on the opioid crisis by offering patients a non-addictive, potent and safe analgesic. With a reduced liability for tolerance and respiratory depression, MTX1604-mediated pain management would be less likely to require dose escalation and, if increased doses were required, could be delivered with less concern for reduced respiratory function. In UG3, the pharmacokinetic (PK) data in multiple preclinical species will be generated to establish a PK/PD relationship of MTX1604, and the data on abuse liability of iv MTX1604 in rats will be expanded. Drug substance, and drug product, for the IND-enabling studies, and early human studies will be manufactured, and appropriately characterized. IND-enabling studies will be completed to secure an open IND for iv-administered MTX1604 for acute pain treatment. The safety, tolerability, and PK profile of MTX1604 will be evaluated in both single- and multiple-ascending dose studies in human volunteers including measuring the effects on pupil constriction as a pharmacodynamic (PD) readout. The key milestones for UG3 are establishing a clear PK/PD relationship pre-clinically, opening an IND and completing a first-in-human study. In UH3, iv MTX1604 will be tested in a validated model of pain, the cold pain test. Once a clear analgesic dose is established, the abuse potential of MTX1604, and its effect on respiratory depression in individuals undergoing hypercapnia, will be evaluated in healthy volunteers. All human studies will include morphine as a comparator. If MTX1604 is well tolerated, and effective, with low abuse potential, and less respiratory depression compared to morphine, it will be advanced into a Phase 2 bunionectomy clinical trial to confirm its analgesic efficacy. The key milestones for UH3 are to determine the PK/PD relationship of MTX1604 in the human cold pain model, and a Phase 2 bunionectomy trial, as well as to evaluate its respiratory safety, and its potential for abuse in humans. Mirata Pharmaceuticals will be contributing significant investment funds in support of both UG3 and UH3 programs and will separately be funding work to develop an oral, or alternative out-patient formulated product (such as pumps and transdermal delivery).